Thursday, October 30, 2014

Last week, in disclosing the company’s quarterly financial report, pharmaceutical giant Biogen revealed that a patient taking its oral MS drug Tecfidera had developed the dreaded brain infection PML and later died of pneumonia (click here). This news understandably created much anxiety in the MS population, particularly among those patients currently taking Tecfidera and those considering starting the drug. Let’s take a careful look at the details of this unfortunate news and try to properly assess its impact.

In the roughly 18 months since it was first approved by the FDA, Tecfidera has become a blockbuster drug, generating nearly $2 billion in sales over the last nine months alone (click here). The tremendous financial success of Tecfidera is in large part due to its ease of use (it’s a pill), relatively high efficacy rates, and a perceived low risk of serious side effects. Until this case of PML was reported, the Tecfidera side effects receiving the most attention were flushing and gastrointestinal distress, both of which subside after 6-8 weeks in the majority of patients taking the drug. Obviously, adding the risk of PML to the equation could change this calculus significantly, so it’s vitally important to parse this new information as best as possible to try and appreciate the true risk posed by PML in the Tecfidera MS population.

It’s essential to understand just what is PML, and how Tecfidera’s mechanism of action might increase the risk of contracting the disease. PML (Progressive Multifocal Leukoencephalopathy) is an infection of the brain and central nervous system that is caused by the JC virus, a pathogen that is present in about 50%-60% of the general population (click here). Under normal circumstances, those carrying the JC virus are completely without symptoms and the virus is kept in check by the human immune system. In patients whose immune systems have been compromised (for instance, people with AIDS), the JC virus can lead to PML, an infection that destroys myelin in large portions of the brain, leading to significant disability, and, in many cases, death. PML is a much-publicized potential side effect of the intravenous MS drug Tysabri, which profoundly suppresses immune system activity in the central nervous system of patients taking the drug, thereby leaving those carrying the JC virus potentially susceptible to the infection. This is why strict testing for JC virus antibodies has been instituted for all patients on Tysabri therapy. PML has also been seen patients with MS as well as other diseases taking other immunosuppressive drugs, as these drugs can, by their very nature, compromise the body’s ability to keep the JC virus under control.

Tecfidera (whose chemical name is dimethyl fumarate) is purported to work through a variety of actions. The drug is thought to have anti-inflammatory and antioxidant properties, but studies have definitively shown that one of the drug’s primary actions is immunosuppression. In trials, Tecfidera was demonstrated to reduce the amount of lymphocytes (infection fighting white blood cells) by about 28% in treated patients (click here, the pertinent information is on page 9). While this level of lymphocyte suppression is not considered to put patients at any kind of serious risk, it could very well account for Tecfidera’s efficacy in treating multiple sclerosis, as the disease is, at least in part, driven by an aberrant immune response.

These same studies also found that about 4% (1 in 25) of patients treated with Tecfidera develop a more serious drop in lymphocyte count, resulting in a condition known as lymphopenia. Severe lymphopenia can indeed open the patient up to opportunistic infections, and for this reason FDA guidelines call for regular blood testing to monitor for the condition in Tecfidera treated patients (click here). Currently, the FDA suggests patients have their blood counts checked once a year, but in practice many neurologists are being far more diligent in testing their Tecfidera treated patients. This recent news about PML and Tecfidera could very well result in more stringent blood testing requirements, but even without such a mandate it seems wise that patients be tested quite regularly to check that their lymphocyte counts remain at safe levels.

Although there currently aren’t many available details on the PML Tecfidera case reported last week by Biogen, it is known that the patient in question had been on Tecfidera for nearly 5 years (she started taking the drug during the approval trials), and had been experiencing severe lymphopenia for 3 ½ years. Logic would seem to dictate that a patient be taken off the drug as soon as their lymphocyte counts drop into dangerous territory, so the fact that this unfortunate soul was left with severe lymphopenia unaddressed for years on end is, to my mind, completely inexplicable. Indeed, it would seem that given the circumstances, her neurologist was courting disaster. Again, I am basing this assessment on scant details, but I have a hard time imagining any scenario that would warrant keeping a patient on a medication that was suppressing their immune system to dangerous levels for such an extended period of time. If the specifics of the case are as originally reported, the fact that the patient was kept on Tecfidera for three and half years after she first tested positive for severe lymphopenia quite frankly boggles the mind.

If anything, this case would seem more to underscore the importance of diligent patient monitoring than any inherent potential danger posed by Tecfidera. Ceasing the drug in the face of troubling blood test results should be a no-brainer. Patients experiencing severe lymphopenia in the Tecfidera trials saw their lymphocyte counts increase significantly within four weeks of stopping the drug. It is currently not known how long is required for lymphocyte counts to return to pre-Tecfidera levels.

While it would be extremely concerning if the patient in question developed PML while her lymphocyte counts remained at acceptable levels, the facts as now known indicate that this simply was not the case. Given the immunosuppressive properties of Tecfidera, it would appear to be vitally important that patients be regularly tested to check their white blood cell counts. It would seem that the FDA suggestion of once yearly blood tests is insufficient, and I know many neurologists are checking their patients much more frequently, more on the order of at least once every three months. Monitoring for JC virus might make sense if PML were to be seen in Tecfidera patients not experiencing severe lymphopenia, but at this point the available evidence doesn't seem to merit the taking of this extra step. Then again, any extra bit of information is valuable, and I'd imagine that some neurologists might Institute testing for JC virus in their Tecfidera patients on their own. Tecfidera is proving to be quite effective in reducing relapse rates and the formation of new brain lesions when used to treat RRMS (click here), and with proper monitoring it would appear that the drug is actually quite safe.. Of course, the drug has only been on the market for a year and a half, and only time will reveal the true long term efficacy and safety of Tecfidera.

As this tragic PML case demonstrates, the fact that Tecfidera can induce severe lymphopenia in 1 out of 25 patients taking it should make both patients and doctors alike keenly aware of the need for proper blood count monitoring. Patients shouldn’t be shy about requesting such tests if their neurologists don’t currently require them. Knowledge is power, folks, and patients need to equip themselves as best as possible with the most accurate data available and take an active role in making treatment choices. The doctor-patient relationship should be a partnership, not a dictatorship. It’s terribly unfortunate that PML has entered the Tecfidera picture, but the case in question seems much more like the exception than the rule. This is not to say that this recent news shouldn’t be cause for concern, but it certainly shouldn’t induce panic among those currently taking the drug or those considering Tecfidera therapy.

It is my fervent hope that future MS therapies will turn away from immunosuppression and find some other more effective, more benign mechanism for fighting the disease. But, as the current crop of drugs are generating billions and billions of dollars in profit for the companies that make them, it will likely be quite some time before my hopes are realized. For now, it is imperative that patients as much as possible use their heads, and, armed with accurate information, work in tandem with their physicians to best beat back the beast that is MS. At this point, Tecfidera appears to be a valuable tool in this quest, but like all tools it needs to be used intelligently and with care.

Hi Daphne, nothing to be embarrassed about, the PML picture is as clear as mud. I'm actually more surprised that people on immunosuppressive drugs don't get more opportunistic infections then they have so far. Seems to me that suppressing the immune system for long periods of time is playing with fire, but I suppose as long as it's not suppressed too much the danger is minimal. How this plays out over years and years has yet to be seen. These days, folks on Tysabri are very stringently monitored for any signs of JC virus activation. I suspect we might start seeing similar protocols imposed on patients taking some of these other, newer, and more potent drugs.

Results: 1. BG-12, tBHQ, SFN and protandim are well-tolerated and strongly induce Nrf2-driven antioxidant enzyme production in oligodendrocytes, with protandim showing the most potent induction. 2. Nrf2 activators are able to protect oligodendrocytes against ROS-induced cytotoxicity. Conclusions: Our findings indicate that several Nrf2 activators are able to significantly increase antioxidant enzyme production in oligodendrocytes. Interestingly, protandim, a dietary supplement consisting of herbal ingredients, was the most potent inducer and therefore may be the most suited as a therapeutic strategy. Importantly, Nrf2-mediated antioxidant enzyme expression in oligodendrocytes resulted in enhanced oligodendrocyte survival during an oxidative attack.

Thanks for your comments. I wrote about Protandim and my attempts, in conjunction with my naturopath, to duplicate the action of this natural supplement by using greater amounts of its ingredients, in a post on these pages several years ago:

At the time that the Protandim study was published not much was known about mechanism of Tecfidera. It now seems that Tecfidera's primary mechanism is immunosuppression, and it's Nrf2 properties (Nrf2 is a powerful chemical pathway in the body that produces strong natural antioxidants) are likely a secondary function.

As I wrote in the piece linked to above, Protandim contains an ingredient that could be detrimental to people with MS (Ashwaganda, which can stimulate the immune system). Also, the study in question tested the substances in a Petri dish, and we have little proof that Protandim can cross the blood brain barrier with enough potency to have any real effect on the central nervous system. At any rate, Protandim is definitely not a substitute for Tecfidera, although some of the ingredients in Protandim certainly may be beneficial to PwMS.

I've been taking higher doses of the good stuff contained in Protandim for several years now, and unfortunately can't report any substantial benefit. That said, I can't say that I wouldn't be faring worse if I wasn't taking these supplements, so who knows? Bottom line, though, is that there really is no equivalency between Tecfidera and Protandim, other than the fact that they both may stimulate the production of antioxidants in the body, which is a good thing.

Yes, I am familiar with this ongoing trial. Unfortunately, it seems to be going slowly. Last I heard they were still enrolling patients. For purposes of the trial, the drug has been designated MN–166. The drug is used in Japan to treat asthma and other bronchial disorders, but is thought to have anti-inflammatory and neuroprotective properties. Hopefully the trials will be successful, but even if this trial is successful they will need to be a further phase 3 trial, so it will be years before this drug hits the market. I'm sure that it must be possible to procure some from Japan through the magic of the Internet, but little is known about its effects on MS…

Biogen should release a statement to the patient population, not only to investors. Outrageous. In addition, we should have more information about the patient's case history, such as prior use of immunosuppressants.

Agreed. It is incredible that we only heard of this case in a financial report. I certainly hope further details will be forthcoming, as the facts as presented seem rather strange. Knowing whether or not the patient had been on prior immunosuppressants would be quite telling, as it's been well demonstrated that the risk of PML in patients taking Tysabri is much higher if they've previously taken immunosuppressant drugs.

Thanks for highlighting this on Tecfidera. I was one of the patients who took this drug- then had to stop due to drastic drop in my body's ability to fight off infection. My Neurologist had me drop the drug immediately (heck, he called me from his car when he received the lab results) We monitored my counts for about 2 months (and I avoided everyone with anything that even resembled a sniffle) until they finally returned to normal. Lucky for me I did not suffer any ill effects. Lucky for me that I have a great neurologist who seems to understand both my disease - and me. He knew how to get the blood tests coded so the insurance picked up their end of the bill and conversed with me via email and phone so I would not have to make multiple visits to his office, which helped me financially since we are on such a tight budget.Unfortunately, insurance often dictates how many and what kind labs they will cover - and they like to cite Federal Mandates (that are meant to be minimum guidelines) as why they have these policies in place. Unless you have discovered a problem (mine was discovered at the one year blood test), getting more than one or two blood tests a year could be problematic unless the patient wants to cover the lab costs themselves. Added to this mix is that many MS patients simply cannot afford this additional cost. Insurance premiums have gone up dramatically over the last few years - but coverage has actually gone down- and out of pocket expense, such as doctor co-pays have gone up, even though what the doctor charged for office visits did not.Not saying there is an easy fix, but would help if Feds made more tighter mandates. I might have had quarterly blood tests and caught the problem sooner. Now I am in the middle of sifting through technical "doctor" language to decide which therapy might work best for me next. My doctor has provided me with a number of avenues to explore. Not only does he speak doctor, insurance and practicality, but he also is pretty good at layman's terminology.

Well, at least it sounds like you have a good neurologist. I suspect that given this news more frequent blood testing may be required of people taking Tecfidera, and that should be covered by insurance. The blood test in question is a simple CBC, which is a standard blood test that can be ordered by any doctor. One way around your insurance problems may be to go to your general practitioner to get the blood test, as your insurance should pay for testing ordered by a different doctor. At least then you might be able to get tested a bit more often.

Very glad to hear that your lymphopenia was caught, and that you didn't suffer any ill effects. Also good to hear that your cell counts returned to normal after two months.

I take Tecfidera. I switched from Copaxone, Nurse Practiononer’s suggestion. She said my disease was still active. It’s been about 2 months. Soul Shine by Allman Brothers in background. I think I’m more wobbly (meaning my MS symptoms are worse.) I am thinking about stopping Tecfidera and just taking something called Digestacure. Now Supertramp in background.

From what I've read, it usually takes Tecfidera about three months to really kick in, so you might want to give it some more time. Of course, be sure to have your lymphocyte counts checked. Not to pooh-pooh any alternative therapies, but if you do indeed have active disease you should probably be on something. Most of the recent research suggests that there is a window of opportunity when treating MS, and most therapies are effective in the early, active stages of the disease. My advice would be to be aggressive and not let the disease really take hold, but of course every patient must make their own risk/reward assessments.

Glad you are enjoying the classic rock. They don't make 'em like that anymore…

Hi Marc--Just wanted to clarify that the Nrf2 pathway is not just anti-oxidant. It also affects the immune system, as evidenced by modulation of t cells. The problem is, we don't understand the long term issues with lymphocyte sequestration. Fumaderm (another DMF compound) had similar issues with PML, in four patients who were on the medication for more than 3 years. Joan http://www.jimmunol.org/content/early/2012/01/16/jimmunol.1101712.full.pdf

Hi Joan, thanks for the link. Interesting stuff, just further proof about how much we don't know about the workings of the immune system. Far more than we do know, actually.

The Fumaderm PML cases were all in patients who were either experiencing long-term severe lymphopenia, or had been previously or concurrently on immunosuppressive drugs. So far, at least, dimethyl fumarate has not been associated with PML in patients whose immune systems weren't showing signs of being severely compromised. Also, given the large number of patients taking Fumaderm in Europe the incidence of PML was really quite tiny. Of course, most Fumaderm patients aren't on the drug long-term, but at least one of the PML patients was.

I agree completely that the consequences of long-term immunosuppression are a very big unknown. However, what is known is that leaving active RRMS untreated is also quite dangerous, and the newer more aggressive therapies do seem to have a dramatic impact on, at the very least, quality of life. Personally, if I were diagnosed with very active RRMS I would probably opt for HSCT, which has been shown to eliminate all signs of disease activity in about 70% of appropriately chosen patients. A draconian approach, yes, but desperate times call for desperate measures.

Thanks for once again wading through corporate docs to share valuable info. If the pharmaceutical companies grew gonads, they would willingly and candidly inform the people who seek treatment and, in doing so, make those corporations obscenely rich. Unfortunately, companies seem to wait until FDA mandates "Dear Doctor" advisories and/or black box or boxed warnings that "drugs that have special problems, particularly ones that may lead to death or serious injury".

From where I sit, it appears that the pharmaceutical companies have plenty in the way of big gonads, and they are already obscenely rich. There is a requirement that severe side effects of any drug be reported to the FDA, so I'm not sure why this PML case wasn't made public until financial disclosure time.

What the pharmaceutical companies really need are a conscience, not larger gonads.

I started Tecfidera last March. A test for JC virus antibodies was required, I want to say, by the drug distributors (I remember I didn't have to pay for it), but I don't remember for sure. I wasn't able to get a prescription before that blood test. But there's a question I never thought to ask. Is it possible to have JC virus antibodies and still test negative? Reading you helps me discover new questions for my neurologist, so I thank you for all you learn and share.

Hi Kate, I believe it is possible to get both false positives and negatives from the JC virus blood test. This is true of most blood tests, but repeated testing should give a clearer picture of your JC virus status.

My daughter has had blood tests for inflammation which came back negative. Can you tell me if inflammation is constant in ms or does it decrease as the symptoms get better which would show a negative result? Thanks

Hi, please keep in mind that I am not a doctor. That said, I'm not sure that a blood test for inflammation would be indicative of multiple sclerosis, one way or the other. The inflammation experienced in MS patients involves the central nervous system, and this wouldn't show up in a typical blood test.signs of inflammation in the nervous system can be picked up via analysis of spinal fluid, or, more commonly, through MRI scans, which will show "enhancing lesions" when the patient is given gadolinium.

Hi Marc, I just stopped Tex's Fedora yesterday after being on it a year and finding out that I test positive for the JC virus. I saw a new neuro who tested me for it. He also said that patients should have their WBC count checked every three months. My last neuro only did it every 6 months. I don't think that is good enough.--especially if you already have naturally low WBC counts like I do.

Patients who are on it should not assume that their neuro tested them for the JC virus when they were started on it. My old neuro never checked me. Now that I know that I have it hanging around in my system while my WBC hovers in the low end of normal, I am not willing to take it. All it would take is a mean case of pneumonia or a regular flare up of EBV, which I get, to make my WBC count drop low enough to let JC cut loose. That just isn't worth it to me. I am going to explore alternative methods.

With all of that said, I think that this is a good drug for people who have a normal WBC count and I would say on it if I did. I am bummed that I have to go off it to be safe, but I just am not willing to risk it.

Hello everyone, I was diagnosed with MS in 2009. All my issues have been sensory. So far to physical disability.I had to stop taking Tecfidera on the 7th after being on the drug since it was released 1 and a half years ago. This was after we started seeing a consistent drop in my Absolute Lymphocyte count. I got down to 600 from a baseline of 1500. I had been getting blood tests once every 3 months or so. It actually was not the 600 count that took me off the drug. It was my CD4/CD8 counts. My neuro was not so much concerned with 600 but wanted to check CD4/CD8. Those numbers were VERY low. CD4 was around 191 and CD8 was 36. Pretty much what you see in AIDS patients. What really sucks is Tecfidera seemed to be working great (maybe too well?). No new progression on my last 2 MRIs. I had one at 6 months after starting Tec and one just this past December. I tolerated Tec very well too. No real side effects except occasional flushing. Now the only flushing that's going to be happing is the rest of my Tec down the toilet. ;-) We are going to wait 30 days to see where my numbers are (hopefully higher) and then it will be another 30 before I see my neuro to discuss next steps. Probably Aubagio. They did draw blood to see if I'm JC+ but I won't know the results for a couple of weeks. My neuro said that from now on they will be checking CD4/CD8 numbers as part of routine blood work. They will also start doing the JC test.

I've been on Copaxone (1 year), Rebif (6 Months), Betaseron (1.3 years) then Tec. Don't think my state warrants Tysabri. Hopefully I can eke out another year or two and something even better might be available.

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Regretfully, due to the high volume of e-mail received and the realities of living with progressive MS, I'll no longer be able to respond to all e-mails sent. I do read each note, and will do my best to answer as many messages as I can.

About Me

I'm Marc, a 53-year-old male, living in New York City with my lovely and wonderful wife Karen. Diagnosed with Primary Progressive Multiple Sclerosis in March of 2003, I now require a wheelchair to get around the city. I like to drive the wheelchair at full speed, thus the moniker "Wheelchair Kamikaze". I've managed to rig a camera to my chair, so I'm able to take videos and still photos from the unique vantage point of a wheelchair, which I intend to post here.
Before getting sick, I was the Director of DVD Production for one of the major international music companies. Yes, I was once a member of the Evil Empire...
Prior to my enlistment in the Evil Empire, I worked as a video producer and editor.
I grew up in New York City, and spent the 1980s in Boston (college and postcollege rock 'n roll craziness). During the 1990s, I lived in South Florida, until I woke up one morning and realized I was living in South Florida, came to my senses, and moved back to New York.
I hope you like my blog...